4-(cyclicaminomethyl)-5-hydroxyindole-3-carboxylic acids and esters thereof



United States Patent 3,510,491 4-(CYCLICAMINOMETHYL)-5-HYDROXYINDOLE-3-CARBOXYLIC ACIDS AND ESTERS THEREOF Malcolm R. Bell, East Greenbush,N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation ofDelaware N0 Drawing. Filed Feb. 2, 1967, Ser. No. 613,456

Int. Cl. C07d 27/56 US. Cl. 260-268 16 Claims ABSTRACT OF THE DISCLOSURECertain 4 (cyclic aminomethyl) hydroxyindole- 3-car-boxylic acids andesters thereof, having hypoglycemic and psychomotor depressant activity,are prepared by the reaction of the appropriateS-hydroxyindole-Ii-carboxylic acid or ester with a secondary amine andformaldehyde.

This invention relates to new indole derivatives and in particular isconcerned with 3-carboxy-4-methyl-5-hydroxyindoles having attached tothe 4-methyl group selected substituted cyclic amino groups, with estersthereof, and with the preparation thereof.

The compounds of the invention are of the formula HOm COOR N h I whereinN=B is 4-hydroxy-l-piperidyl, 4-oxo-1-piperidyl, 3 hydroxy 8nortropanyl, or 4 lower alkyl 1- piperazinyl; R and R are hydrogen,lower-alkyl or phenyl-loWer-alkyl; and R is hydrogen or lower-alkyl.

In the foregoing definitions the term lower-alkyl refers to alkyl groupshaving from one to about six carbon atoms, thus including, for example,methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, and the like.

The compounds of Formula I above are prepared by reacting a compound ofthe formula HOG ll 11 with formaldehyde and a secondary amine of theformula HN=B. The reaction takes place readily at temperatures betweenabout 50 and 150 C. in the inert solvent. A preferred solvent is aqueousacetic acid.

The structures of the compounds of the invention were established byelementary analysis, by the modes of preparation and by ultraviolet,infrared and nuclear magnetic resonance spectra. The position of the CHN=B group in Formula I was established by degradation studies on thecompound where R is ethyl, R is hydrogen, R is methyl and N=B isdimethylarnino. Treatment of the latter with Raney nickel in refluxingalcohol gave an indole derivative which must be2,4-dimethyl-3-carbethoxy- S-hydroXyindole since it was diiferent fromthe known 2,6 dimethyl 3 carbethoxy 5 hydroxyindole. The NMR spectrawere also characteristic of compounds where there are protons bearing a1,2-relationship on a benzene ring. This indicates that the 6 and 7positions, and not the 4 and 7 positions, are unsubstituted.

COOR

The compounds of the invention are basic in nature and thus formacid-addition salts when treated with moderate to strong inorganic ororganic acids. Although pharmaceutically acceptable, water-soluble saltsare preferred, all salts are useful as intermediates in the preparationof and as characterizing derivatives of the free bases. Theacid-addition salts are the full equivalents of the corresponding freebases claimed herein insofar as the physiological properties inherent inthe cation are concerned. Both the free bases and salt forms areconsidered to be one and the same invention.

Pharmacological testing of the compounds of the invention hasdemonstrated that they possess hypoglycemic and psychomotor depressantactivities, thus indicating their usefulness as insulin substitutes forthe treatment of diabetic conditions, and as sedatives ortranquillizers.

The compounds are prepared for use by dissolving a pharmaceuticallyacceptable salt form in sterile aqueous medium for parenteraladministration; or by formulating a compound of the invention in tabletform with conventional excipients for oral administration.

The following examples will further illustrate the invention without thelatter being limited thereby.

EXAMPLE 1 2-methyL3-carbethOXy-4-( l-hydroxy-1-piperidylmethyl)-S-hydroxyindole A solution of 5 g. (0.0228 mole) of 2-methyl-3-carbethoxy-S-hydroxyindole, 2.05 g. (0.0205 mole) of 4-hydroxypiperidineand 1.82 ml. (0.024 mole) of Formalin (395 mg. of formaldehyde per ml.)in 20 ml. of acetic acid and 5 ml. of water was heated on a steam bathfor thirty minutes, then diluted with 200 ml. of Water and filtered. Thefiltrate was made basic by addition of solid potassium carbonate andextracted with methylene chloride. The extracts were dried andconcentrated to remove the solvents, affording 6.5 g. of2-methyl-3-carbethoxy-4- (4 hydroxy 1 piperidylmethyl) 5 hydroxyindole,M.P. 161-162.5 C. when recrystallized from ethyl acetate. Treatment of asample of the free base with alcoholic hydrogen chloride afforded thehydrochloride salt form, M.P. 204-205 C. (dec.) after recrystallizationfrom water.

EXAMPLE 2 2 methyl 3 carbomethoxy 4 (4 hydroxy 1-piperidylmethyl)-5-hydroxyindole was prepared from 2- methyl 3carbomethoxy 5 hydroxyindole, 4 hydro-xypiperidine and formaldehydeaccording to the procedure of Example 1. The product was obtained in theform of colorless needles, M.P. 189l90 C. (dec.) when recrystallizedfrom ethanol.

EXAMPLE 3 2 methyl 3 carbobenzoxy 4 (4 hydroxy lpiperidylmethyl) 5hydroxyindole was prepared from 2 methyl 3 carbobenzoxy 5 hydroxyindole,4 hydroxypiperidine and formaldehyde, and was obtained in the form ofits hydrochloride salt, M.P. 2ll-2l3 C. (dec.) when recrystallized fromethanol.

The intermediate 2 methyl 3 carbobenzoxy 5- hydroxyindole, M.P. 205207C., was prepared by reacting p-benzoquinone and benzyl B-aminocrotonate.

EXAMPLE 4 2-methyl-4- (4-hydroxy- 1- piperidylmethyl -5-hydroxyindole-3-carboxylic acid A solution of 3.92 g. of2-methyl-3carbobenzoxy-4- (4-hydroxy-l-piperidylmethyl) 5 hydroxyindolehydro- EXAMPLE 5 1,2-dimethyl-3-carbethoXy-4-(4-hydroxy 1piperidylmethyl)-5-hydroxyindole was prepared from 1,2-dimethyl-3-carbcthoxy 5 hydroxyindole, 4-hydroxypiperidine and formaldehyde andwas obtained in the form of colorless needles, MP. 155 .5-159" C. whenrecrystallized from ethanol; and also in the form of its acetic acidsalt, colorless needles, M.P. 147-149" C, when recrystallized fromisopropyl alcohol.

EXAMPLE 6 l-benzyl-Z-methyl 3 carbethoxy 4 (4hydroxy-lpiperidylmethyl)-5-hydroxyindole was prepared from 1-benzyl-2-methyl-3-carbethoxy 5 hydroxyindole, 4-hydroxypiperidine andformaldehyde, and was obtained in the form of its hydrochloride salt,M.P. 2005-2015 C. (dec.) when recrystallized from methanol-ether.

EXAMPLE 7 2-ethyl-3-carbethoxy 4 (4 hydroxy 1piperidylmethyD-S-hydroxyindole was prepared from 2-ethyl-3- carbethoxy5 hydroxyindole, 4 hydroxypiperidine and formaldehyde, and had the MP.148.5150 C. when recrystallized from ethyl acetate.

EXAMPLE 8 3-carbethoxy-4-(4-hydroxy 1 piperidylmethyD-S-hydroxyindolewas prepared from 3-carbethoxy-5-hydroxyindole, 4-hydroxypiperidine andformaldehyde, and was obtained in the form of a pale yellow solid, MP.164 165 C. when recrystallized from ethyl acetate-hexane.

EXAMPLE 9 2 methyl- 3-carbethoxy-4-(4-oxo-l-piperidylmethyl)-S-hydroxyindole was prepared from 2-methyl-3-carbethoxy-S-hydroxyindole,4-piperidone and formaldehyde, and was obtained in the form of itshydrochloride salt, M.P. 202-204 C. (dec.) when recrystallized fromacetic acid.

EXAMPLE l 2-methyl-3-carbethoXy-4-(3,8-hydroxy 8nortropanylmethyl)--hydroxyindole was prepared from 2-methyl-3-carbeth0Xy-5-hydroxyindole, 3/3 -hydroxynortropane and formaldehyde, andwas obtained in the form of its hydrochloride salt, M.P. 247-249 C.(dec.) when recrystallized from methanol-ether.

EXAMPLE ll 2-methyl-3-carbethoxy 4(3a-hydroXy-8-nortropanylmethyl)-5-hydroxyindole was prepared from2-methyl-3- carbethoxy-S-hydroxyindole, 3a hydroxynortropane andformaldehyde, and was obtained in the form of its hydrochloride'salt,colorless needles, M.P. 197.5199 C. (dec.) when recrystallized from 95%ethanol.

EXAMPLE l2 2-methyl-3-carbethoxy 4 (4-methyl 1piperazinylmethyl)-5-hydroxyindole was prepared from 2-methyl-3-carbethoxy 5 hydroxyindole, N methylpiperazine and formaldehyde, and hadthe MP. 991l1 C. when recrystallized from benzene. An acetone solutionof the free base was treated with an acetone solution ofp-toluene-sulfonic acid. The salt which separated Was recrystallizedfrom methanol-ether to give 2-methyl-3-carbethoXy-4-(4-methyl-l-piperazinylmethyl)-5-hydroxyindole in the form of itsp-toluene-sulfonate salt, colorless plates, MP. 197- 201 C.

By replacing the N-methylpiperazine in the foregoing preparation byN-butylpiperazine, there can be obtained 2-methyl-3-carbethoxy4-(4butyl-l-piperazinylmethyl)- S-hydroxyindole.

Similarly, I benzyl-2-mehtyl-3-carboisopropoXy-5-hydroxyindole,1-benzyl-2-methyl-3-carboheXoxy-5-hydr0xyindole,1-benzyl-2-'butyl-3-carbethoxy-S-hydroxyindole,lisopropyl-2-methyl-3-carbethoxy-S-hydroxyindole, 1 (3-phenylpropyl)-2-methyl-3-carbethoxy-S-hydroxyindole or1-(4-phenylbutyl)-2-methyl-3-carbethoxy 5 hydroxyindole can be caused toreact with 4-hydroxypiperidine and formaldehyde to give, respectively,1-benzyl-2-methyl-3- carboisopropoxy-4-(4-hydroXy 1 piperidyl-methyl)-5hydroxyindole, l-benzyl 2 methyl-3-carbohexoXy-4-(4-hydroxy-l-piperidylmethyl)-5-hydroxyindole, l-benzyl-Z-butyl-3-carbethoXy-4-(4-hydroxy 1 piperidylmethyl)-5- hydroxyindole,l-isopropyl 2 methyl-3-carbethoxy-4-(4- hydroxy-l-piperidyl-methyl) 5hydroxyindole, 1- (3- phenylpropyl)-2-rnethyl-3-carbethoxy 4(4-hydroxy-1- piperidylmethyl) 5 hydroxyindole, or 1-(4-phenylbutyl)-2-methyl3-carbethoXy-4-(4hydroxy-l-piperidylmethyl)-5-hydroxyindole.

I claim:

1. A compound of the formula wherein N=B is 4-hydroxy-1-piperidyl,4-oxo-1-piperidyl, 4-oxo-1-piperidyl,3-hydroxy-8-nortropanyl or4-lower-alkyl-l-piperazinyl; R and R are hydrogen, lower-alkyl orphenyl-lower-alkyl; and R is hydrogen or lower-alkyl.

2. A compound according to claim 1 wherein N=B is 4-hydroXy-l-piperidyl.

3. Z-methyl 3carbethoxy-4-(4-hydroxy-l-piperidylmethyl)-5-hydroxyindole, according toclaim 2 wherein R is ethyl, R is hydrogen and R is methyl.

4. 2-methyl-3-carbomethoXy-4-(4-hydroxy 1piperidylmethyl)-5-hydroxyindole, according to claim 2 wherein R and Rare methyl and R is hydrogen.

5. 2-methyl-3-carbobenzoxy-4-(4-hydroxy 1piperidylmethyl)-5-hydroxyindole, according to claim 2 wherein R isbenzyl, R is hydrogen and R is methyl.

6. 2-methyl-4-(-hydroxy 1 piperidylmethyl)-5-hydroxyindole-3-carboxylicacid, according to claim 2 wherein R and R are hydrogen and R is methyl.

7. 1,2-dimethyl-3-carbethoXy-4-(4-hydroxy 1piperidylmethyl)-5-hydroxyindole, according to claim 2 wherein R isethyl and R and R are methyl.

8. 1-benzyl-2-methyl 3 carbethoxy-4-(4-hydroxy-1-piperidylmethyl)-5-hydroxyindole, according to claim 2 wherein R isethyl, R is benzyl and R is methyl.

9. 2-ethyl-3-carbethoXy-4-(4-hydroxy 1 piperidylmethyl)-5-hydroxyindole,according to claim 2 wherein R and R are ethyl and R is hydrogen.

10. 3-carbethoxy-4-(4-hydroxy 1 piperidylmethyl)- S-hydroxyindole,according to claim 2 wherein R is ethyl and R and R are hydrogen.

11. A compound according to claim 1 wherein N B is 4-oxo-1-piperidyl.

12. 2 methy1-3-carbethoxy-4-(4-oxo-1-piperidylmethyl)-5-hydroxyindole,according to claim 11 wherein R is ethyl, R is hydrogen and R is methyl.

13. A compound according to claim 1 wherein N=B References Cited is3-hydroxy-8-nortropanyl.

1 4. 2-methyl 3 carbethoxy-4-(3-hydroxy-8-nortro- UNITED STATES PATENTSpanylmethyl)-5-hydroxyindole, according to claim 13 2,852,527 9/1958Stack- 260*319 wherein R is ethyl, R is hydrogen and R is methyl.

15. A compound according to claim 1 wherein N=B 5 HENRY JILES PnmaryExaminer is 41ower-a1kyl-l-piperazinyl. G. T. TODD, Assistant Examiner16. 2-methyl-3-carbethoxy-4(4-methyl-1-piperazinylmethyl)-5-hydroxyindole, according to claim 15wherein N=B is 4-methyl-1-piperazinyl, R is ethyl, R is hydro- 10 294294.3 326.13 gen and R is methyl.

